Determining the role of Xist long noncoding RNA in hematopoiesis and hematologic malignancies

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2022

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Abstract

X chromosome inactivation (XCI) is a mammalian dosage compensation phenomenon by which expression of X-linked genes is equalized between females and males. Initiation of XCI depends on Xist long noncoding RNA (lncRNA), which triggers transcriptional silencing of one of the two X chromosomes in female cells, except for genes that escape XCI. The inactive state of the X chromosome is maintained throughout subsequent cell divisions with continuous Xist expression. Proper maintenance of XCI in somatic cells is essential for female health, and its disruption has been observed in many diseases. However, whether Xist is required for maintaining XCI and how XCI alterations lead to diseases still remain open questions. Emerging evidence has revealed that the hematopoietic system consists of cells with variable XCI patterns and is highly sensitive to Xist depletion. This makes the hematopoietic system a good model for studying the functional role of Xist during XCI maintenance. By deleting Xist in hematopoietic stem cells (HSCs) of mice, I showed that Xist loss leads to lineage-specific cell cycle and differentiation defects in hematopoietic progenitor cells of female mice. At the molecular level, I showed that Xist loss results in upregulated expression of several X-linked genes, large proportion of which are XCI escape genes. In addition, many transcriptionally upregulated X-linked genes have been implicated in cell cycle- and immune-related functions. Furthermore, transcriptional upregulation of X-linked genes in Xist-deficient cells is accompanied with a series of epigenetic changes on the inactive X chromosome (Xi) including reduced density of repressive histone marks, increased density of active histone modifications, and enhanced chromatin accessibility which accommodates increased binding of a transcription factor, Ying Yang 1 (YY1). Collectively, these findings suggest a critical role of Xist in regulating expression level of X-linked genes with essential hematopoietic functions during XCI maintenance.

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Yang, Tianqi (2022). Determining the role of Xist long noncoding RNA in hematopoiesis and hematologic malignancies. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/26784.

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